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Journal of Lipid Research, Vol. 43, 1400-1409, September 2002
Copyright © 2002 by Lipid Research, Inc.

Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse

Lionel Clément^*, Hélène Poirier^*, Isabelle Niot^*, Virginie Bocher, Michèle Guerre-Millo, Stéphane Krief^**, Bart Staels and Philippe Besnard^1,*

^* Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation (ENSBANA) FRE2328 CNRS-CESG/Université de Bourgogne F- 21000, Dijon, France
Département d'Athérosclérose/U545 INSERM, Institut Pasteur de Lille, F-59019 Lille and Faculté de Pharmacie, Université de Lille II, Lille, France
U.465 INSERM, Institut Biomédical des Cordeliers, F-75006 Paris, France
^** Bioprojet Biotech, 4 rue du Chesnay-Beauregard, F-35760 Saint Grégoire, France

¹ To whom correspondence should be addressed. e-mail: pbesnard{at}u-bourgogne.fr

Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass in mice, but also causes considerable liver steatosis. However, little is known of the molecular mechanisms leading to hepatomegaly. Although c9,t11- and t10,c12-CLA isomers are found in similar proportions in commercial preparations, the respective roles of these two molecules in liver enlargement has not been studied. We show here that mice fed a diet enriched in t10,c12-CLA (0.4% w/w) for 4 weeks developed lipoatrophy, hyperinsulinemia, and fatty liver, whereas diets enriched in c9,t11-CLA and LA had no significant effect. In the liver, dietary t10,c12-CLA triggered the ectopic production of peroxisome proliferator-activated receptor (PPAR), adipocyte lipid-binding protein and fatty acid transporter mRNAs and induced expression of the sterol responsive element-binding protein-1a and fatty acid synthase genes. In vitro transactivation assays demonstrated that t10,c12- and c9,t11-CLA were equally efficient at activating PPAR, ß/, and and inhibiting liver-X-receptor.

Thus, the specific effect of t10,c12-CLA is unlikely to result from direct interaction with these nuclear receptors. Instead, t10,c12-CLA-induced hyperinsulinemia may trigger liver steatosis, by inducing both fatty acid uptake and lipogenesis.

Abbreviations: ALBP, adipocyte lipid-binding protein; CLA, conjugated linoleic acid(s); FAS, fatty acid synthase; FAT/CD36, fatty acid transporter; LA, linoleic acid; L-FABP, liver fatty acid-binding protein; LXR, liver-X-receptor; PEPCK, phosphoenol-pyruvate carboxykinase; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol responsive element-binding protein; 22R-CS, 22(R)-hydroxycholesterol; WAT, white adipose tissue

Supplementary key words conjugated linoleic acid • peroxisome proliferator-activated receptors • liver-X-receptors • sterol responsive element-binding proteins • hyperinsulinism • liver steatosis

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